Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19

Abstract

Objective:To test the hypothesis that COVID-19 has an impact on the CNS by measuring plasma biomarkers of CNS injury.Methods:We recruited 47 patients with mild (n=20), moderate (n=9) or severe (n=18) COVID-19 and measured two plasma biomarkers of CNS injury by Single molecule array (Simoa): neurofilament light chain protein (NfL) (a marker of intra-axonal neuronal injury) and glial fibrillary acidic protein (GFAp) (a marker of astrocytic activation/injury) in samples collected at presentation and again in a subset after a mean of 11.4 days. Cross-sectional results were compared with 33 age-matched controls derived from an independent cohort.Results:The patients with severe COVID-19 had higher plasma concentrations of GFAp (p=0.001) and NfL (p<0.001) than controls, while GFAp was also increased in patients with moderate disease (p=0.03). In severe patients an early peak in plasma GFAp decreased upon follow-up (p<0.01) while NfL showed a sustained increase from first to last follow-up (p<0.01), perhaps reflecting a sequence of early astrocytic response and more delayed axonal injury.Conclusion:We show neurochemical evidence of neuronal injury and glial activation in patients with moderate and severe COVID-19. Further studies are needed to clarify the frequency and nature of COVID-19-related CNS damage, and its relation to both clinically-defined CNS events such as hypoxic and ischemic events and to mechanisms more closely linked to systemic SARS-CoV-2 infection and consequent immune activation, and also to evaluate the clinical utility of monitoring plasma NfL and GFAp in management of this group of patients.

Reply to the Letter “COVID‐19‐Associated Encephalopathy and Cytokine‐Mediated Neuroinflammation”

“…ICANS is a neuropsychiatric syndrome with heterogeneous clinical manifestations; however, akinetic mutism is a recurrent and specific feature that might help discriminate it from other encephalopathies. 2,3 Interestingly, we observed 3 COVID-19 patients presenting with a similar phenotype to Pilotto et al's case, including transitory akinetic mutism, where other likely causes were reasonably excluded and SARS-CoV-2 real-time polymerase chain reaction in CSF tested negative (unpublished data).…”

“…1 Neurotoxicity grade in ICANS correlates with CSF cytokine levels, including IL-8, TNF-α, and IL-6, and not with CAR-Ts or WBC in CSF, suggesting a causative role of the former. 3 Specifically, IL-8 was found significantly increased in the CSF relative to blood, consistent with local CNS production in ICANS. 3 Pilotto et al's patient had mild systemic inflammation; thus, although matched serum and CSF cytokines were not reported, it is feasible to suspect that the IL-8 CSF/serum ratio would have been elevated.…”

“…Diffuse slowing on electroencephalogram, unremarkable brain magnetic resonance imaging, and mildly elevated white blood cell count (WBC) and protein levels in CSF are common findings in ICANS, 2,3 and were also observed in Pilotto et al's case. 1 The authors described elevated CSF interleukin (IL)-8 and tumor necrosis factor (TNF)-α levels that decreased with clinical improvement, whereas WBC remained stable.…”

“…5 ICANS usually resolves on its own; however, corticosteroids are the first-line therapy for severe cases. 2,3 The overlapping features of this case report and neurotoxicity related to CAR-T therapy bring into question the possibility of a shared, cytokine-mediated pathophysiology, which can further inform treatments. Muccioli et al proposed an interesting comparison between the case of encephalitis related to severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) infection we described and immune effector cell-associated neurotoxicity syndrome (ICANS).…”

Miller‐Fisher syndrome after COVID‐19: neurochemical markers as an early sign of nervous system involvement

“…With the spreading of the SARS-CoV-2 pandemic worldwide, more such cases will probably be described. Measurement of NfL in the blood might be considered an easy tool to detect early affection of the peripheral and central nervous system [6,7].…”